A deficiency in acid beta-glucosidase (betaGlc) causes Gaucher disease, which ranges in severity from a neurologically devastating disease in infancy to a mild disease in adulthood. A thorough understanding of the mechanisms that control betaGlc expression is necessary to design future therapeutic interventions, particularly gene therapy. this proposal aims to elucidate the regulation of betaGlc expression, placing particular emphasis on neural cells and cells of the monocyte/macrophage lineage, which are adversely affected in Gaucher disease. Specifically, we will determine: (1) What mechanisms control basal levels of betaGlc activity in different tissues? We have shown already that betaGlc mRNA expression plays a major role in differential betaGlc expression. We now plan to determine the role of protein turnover in regulating betaGlc activity, and to elucidate the role of transcription and mRNA stability in controlling betaGlc mRNA levels. We also plan to identify the sequences that control betaGlc mRNA levels, and the proteins that bind these elements. Preliminary results indicate that the betaGlc promoter contains elements that are recognized by tissue specific and ubiquitous factors. (2) Does feedback regulation control betaGlc gene expression? BetaGlc activity in vivo increases in response to procedures that increase substrate level. We will establish an in vitro model in which the role of substrate accumulation on betaGlc expression can be evaluated. (3) How is betaGlc activity regulated in the developing nervous system? BetaGlc activity is high in mouse fetal brain and declines in the neonate. Using the mouse as a model system, betaGlc activity and mRNA levels will be measured during brain development. We will investigate how changes in the amounts of the transcription factors identified in aim #1 may influence betaGlc expression in vivo in the brain. Also, because it is possible that the developmental regulation of betaGlc may be driven by substrate levels, changes in the factors that control feedback regulation in neural cells elucidated in aim #2 also will be investigated. A detailed understanding of the control of betaGlc expression in neural cells has important implications not only for gene therapy of severe Gaucher disease, but also for the treatment of other neurological diseases that require gene expression in multiple cell types.